tbuckley/cabot-search huggingface dataset:
Abstract 5551: Cancer associated PSA-glycoforms as prostate cancer markers
Authors: Hannu Koistinen, Ruusu-Maaria Kovanen, Timo-Pekka Lehto, Antti Rannikko, Tuomas Mirtti
Journal: Cancer Research (2023)

Abstract Changes in protein glycosylation have been observed in several cancers, where they affect cellular growth behavior, invasiveness and acquisition of metastatic potential. Such changes are not random and have been found to associate with cancer aggressiveness. Thus, detection of protein glycosylation may offer novel opportunities for cancer biomarker development. Since prostate-specific antigen (PSA) is glycosylated, assessing different PSA-glycoforms may provide valuable diagnostic and prognostic information. We recently established a novel in situ proximity ligation-based method for the detection of different protein-glycoforms in tissue sections. This method utilizes protein-specific antibody and glycan-binding lectins. We have optimized this method for the detection of different PSA-glycoforms in formalin-fixed paraffin-embedded prostatic tumor samples. We found that PSA is, indeed, differently glycosylated in prostate cancer (n=23) compared to benign prostate tissue (n=4). Two of the 25 studied lectins showed prominent staining only in cancer tissues (p&amp;lt;0.0001 for both), although the total PSA staining was stronger in benign tissues (p=0.006). We are currently validating these results in large, well-curated clinical cohorts, with intention to test whether PSA-glycoforms in tissue offer improved detection of clinically significant prostate cancer. These studies facilitate development of tools for identification of cancer-specific PSA-isoforms in serum samples. Detection of such isoforms is likely to provide independent diagnostic and prognostic information. Citation Format: Hannu Koistinen, Ruusu-Maaria Kovanen, Timo-Pekka Lehto, Antti Rannikko, Tuomas Mirtti. Cancer associated PSA-glycoforms as prostate cancer markers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5551.
Abstract 6316: In vitro and in vivo studies of human granzyme B fusion constructs targeting mesothelin
Authors: Khalid A. Mohamedali, Lawrence H. Cheung, Louis R. DePalatis, Claire Thuning-Roberson, Michael G. Rosenblum
Journal: Cancer Research (2023)

Abstract Mesothelin is highly expressed on tumor cells and promotes tumor growth and drug resistance. Pancreatic, ovarian, mesothelioma, and lung cancers highly express mesothelin and are cancers of unmet needs with ≤16% relative 5-year survival using standard of care. When delivered to tumor cells by immune effector cells, granzyme B (GrB) is a highly cytotoxic serine protease which induces apoptosis through both caspase-dependent and -independent mechanisms. We developed a fusion protein (GrB-Fc-SD1) composed of human GrB and containing SD1, a novel human single-domain antibody that uniquely targets Region III of the glycoprotein, mesothelin. The SD1 and GrB domains are connected by a human IgG heavy chain fragment which enables dimerization. Thus, the increase in total construct molecular weight leads to an increased in vivo circulation time and anti-tumor efficacy. GrB-Fc-SD1 was transiently expressed in HEK-293E cells under serum-free conditions and purified to homogeneity to a final yield of approximately 5 mg/L. Anti-GrB western blot analysis confirmed the expression of GrB-Fc-SD1 exclusively as a dimer. Comparison of GrB-Fc-SD1 with its expected molecular weight suggests significant glycosylation when produced in HEK-293E cells. The enzymatic activity of granzyme B in GrB-Fc-SD1 was comparable to that of commercially available human granzyme B. In vitro cytotoxicity against a limited panel of lung, pancreatic and ovarian cancer cell lines expressing surface mesothelin indicate cytotoxicity in the nanomolar range, while cytotoxicity against mesothelin-negative cells was at micromolar levels. GrB-Fc-SD1 bound specifically to mesothelin extra-cellular domain compared to a non-specific control, as determined by ELISA. Biacore analysis confirmed binding with a dissociation constant between 10−7 to 10−8 M. These data warrant continued investigation of the protein as a therapeutic candidate. Accordingly, ex vivo serum stability studies are underway. In addition, screening of an expanded panel of tumor cell lines for in vitro cytotoxicity is currently in progress and will be reported. In vivo efficacy studies against nude mice bearing Capan-2 xenograft models are currently underway and will also be reported. Research supported by H2Biologics. Research conducted, in part, by the Clayton Foundation for Research. Citation Format: Khalid A. Mohamedali, Lawrence H. Cheung, Louis R. DePalatis, Claire Thuning-Roberson, Michael G. Rosenblum. In vitro and in vivo studies of human granzyme B fusion constructs targeting mesothelin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6316.
Abstract 38: PBMC donor selection affects engraftment rates and onset of graft versus host disease in humanized NCG mice for use in cancer studies
Authors: Steven Bronson, Jenny Rowe, Christoph Eberle, Stephen Festin
Journal: Cancer Research (2023)

Abstract Preclinical studies examining tumor biology and immunity are limited by differences between the mouse and human immune systems. Humanized mouse models offer a unique tool to assess the anti-tumor response by recapitulating aspects of human tumor biology. Humanized mice are created by injecting either human CD34+ hematopoietic stem cells or peripheral blood mononuclear cells (PBMCs) into an immunodeficient mouse strain. Here we utilized a PBMC humanized NCG mouse model to investigate human T-cell mediated anti-tumor response (&amp;gt;95% CD3+ T-cells by day 21). The challenges encountered with this model include the onset of graft versus host disease (GvHD) and donor variability leading to donor specific engraftment rates. Consistency is required with humanized PBMC models to ensure their use as an appropriate research model. Therefore, we examined the relationship between donor selection and engraftment rates as well as the onset of GvHD. Inter-donor variability was assessed by collecting PBMCs from multiple healthy donors. Intra-donor consistency was assessed by collecting PBMCs from the same donors at subsequent collections and comparing to initial human immune cell profiling by flow cytometry. NCG mice were injected with 1 × 107 PBMCs from individual donors. Animals were weighed three times a week to monitor for changes in body weight and general health status. Peripheral blood was collected at day 9, 21 and 42 for flow cytometry screening of human immune cell engraftment (hCD45+, hCD3+, hCD4+ and hCD8+) at the initial collection. Human PBMCs isolated from additional collections from the same donors were also injected into NCG mice and flow cytometry was performed on the new cell lots at day 21. Donors were grouped into categories based on engraftment rates, which were donor dependent. Donor variability is an important aspect to consider when humanizing mice with human PBMCs. PBMC humanized models are important for the study of pre-clinical therapeutics, but donor engraftment rates must be considered when engrafting the mice to create a consistently humanized mouse. Citation Format: Steven Bronson, Jenny Rowe, Christoph Eberle, Stephen Festin. PBMC donor selection affects engraftment rates and onset of graft versus host disease in humanized NCG mice for use in cancer studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 38.
Abstract 2736: Locoregional modified vaccinia ankara (MVA) encoding a single-chain IL-12 achieves efficacy antitumor immune response in peritoneal carcinomatosis
Authors: Ángela Bella, Leire Arrizabalaga, Claudia Augusta Di Trani, José González-Gomariz, Assunta Cirella, Irene Olivera, Maite Alvarez, Álvaro Teijeira, Cigdem Atay Langbein, José Medina-Echeverz, Maria Hinterberger, Hubertus Hochrein, Ignacio Melero, Pedro Berraondo, Fernando Aranda
Journal: Cancer Research (2023)

Abstract Peritoneal carcinomatosis is an advanced stage of cancer developed in the peritoneal cavity without effective treatment. In order to restore antitumor immunity subverted by tumor cells, we evaluated in this study intraperitoneal administration of vaccinia virus Ankara (MVA) genetically modified to express the proinflammatory cytokine single-chain interleukin 12. MVA encoding scIL-12 was evaluated in peritoneal carcinomatosis models based on intraperitoneal administration of tumor cells. The immune response was evaluated by ELISpot, flow cytometry, intravital microscopy, and depleting monoclonal antibodies. Safety was assessed by measuring body weight and a hemogram test. Tissue tropism after intravenous or intraperitoneal administration was determined by bioluminescence analysis after the administration of MVA encoding luciferase. Intraperitoneal or locoregional administration, but not other routes of administration, elicited a potent immune response characterized by increased levels of tumor-specific T CD8 lymphocytes. The antitumor immune response was detectable not only in the peritoneal cavity but also systemically. As a result, a single intraperitoneal administration of MVA encoding scIL-12 completely eradicates MC38 cells implanted in the peritoneum, protecting cured mice from a subcutaneous rechallenge with MC38 cells. The safety profile of intraperitoneal administration was also superior to that of intravenous administration since there was no weight loss or hematological toxicity when the vector was infused into the peritoneal cavity. In conclusion, intraperitoneal administration of MVA vectors encoding scIL-12 induces a potent tumor-specific immune response that leads to the eradication of peritoneal metastasis. Citation Format: Ángela Bella, Leire Arrizabalaga, Claudia Augusta Di Trani, José González-Gomariz, Assunta Cirella, Irene Olivera, Maite Alvarez, Álvaro Teijeira, Cigdem Atay Langbein, José Medina-Echeverz, Maria Hinterberger, Hubertus Hochrein, Ignacio Melero, Pedro Berraondo, Fernando Aranda. Locoregional modified vaccinia ankara (MVA) encoding a single-chain IL-12 achieves efficacy antitumor immune response in peritoneal carcinomatosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2736.
Abstract 1715: SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer
Authors: Matthew J. Sale, Neal Mukherjee, Regina Ruzicka, Robin Jacob, Christoph Albrecht, Teresa Zanin, Tom Madensky, Kaja Kostyrko, Robyn L. Schenk, Anke Baum, Daniel Gerlach, Marco H. Hofmann, Frank McCormick
Journal: Cancer Research (2023)

Abstract SOS1 is a principal guanine nucleotide exchange factor for canonical RAS GTPases and activates RAS signaling. Mutations in SOS1 are found in 3-5% of non-small cell lung cancers (NSCLC), colorectal cancers (CRC) and melanomas. The recent development of novel SOS1 inhibitors, including BI-3406 and BI-1701963, that block interaction between SOS1 and RAS, presents a potential therapy for SOS1-driven cancers. Here we show that the majority of SOS1 mutations observed in patients enhance RAS guanine nucleotide exchange in cells and activate RAS-MAPK signaling. Of the 11 available SOS1-mutant cancer cell lines without RAS co-mutation, 10 were sensitive to SOS1 inhibition in 2D and/or 3D cell culture, while cells with SOS1 and RAS co-mutations were resistant to SOS1 inhibition. Treatment with a SHP2 inhibitor, which is presumed to inhibit the activity of both SOS1 and SOS2, revealed a subset of SOS1-mutant cell lines that were more sensitive to SHP2 inhibition than SOS1 inhibition. This implied that, in certain settings, SOS2 can compensate for the loss of SOS1 activity. Accordingly, these cells exhibited a rebound in RAS signaling after treatment with SOS1i that was dependent on SOS2. SOS2 knock-down further sensitized these cells to SOS1 inhibition, resulting in responses equivalent to SHP2 inhibition. In addition, we show that, as with SOS1, SOS2 is a target for ERK1/2-dependent feedback phosphorylation. Thus, relief of ERK1/2-dependent negative regulation of SOS2, following SOS1 inhibition, likely contributes to receptor tyrosine kinase (RTK)-SOS2 activation that may mediate SOS1 inhibitor resistance in some contexts. In vivo, SOS1i inhibited tumor growth in xenograft models of SOS1-mutant AML and NSCLC. Tumor-suppressive effects of SOS1i in these models were comparable to or stronger than the effects of SHP2i or MEKi. Thus, our results suggest that SOS1 inhibition could be an effective therapeutic approach in RAS wild-type cancer patients with SOS1 mutations. Citation Format: Matthew J. Sale, Neal Mukherjee, Regina Ruzicka, Robin Jacob, Christoph Albrecht, Teresa Zanin, Tom Madensky, Kaja Kostyrko, Robyn L. Schenk, Anke Baum, Daniel Gerlach, Marco H. Hofmann, Frank McCormick. SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1715.
Abstract 2670: Drug combinations against Barrett's stem cells show efficacy across advanced lesions in esophageal cancer
Authors: Wa Xian, Jennifer Lin, Mona Oraei, Frank McKeon, Shan Wang, Jaffer Ajani, Christopher Crum, William Bachovchin, Melina Khorrami, Amber Su, Melika Khorrami, Shumei Song, Jeremy Siegelman, Matt Vincent, Khek Yu Ho, Yusuke Yamamoto
Journal: Cancer Research (2023)

Abstract We have applied a single cell cloning technology to patient-matched endoscopic biopsies of Barrett's esophagus and co-existing lesions of low-grade dysplasia (LGD), high-grade dysplasia (HGD), and esophageal adenocarcinoma (EAC). In vitro differentiation and xenografting of these clones yields epithelia with histology corresponding to the origin of these clones, and the EAC clones yield aggressive tumors in vivo. In addition, genomic analyses of these clones reveals their phylogenetic relationships based on common and accumulating mutations. In efforts to identify drugs that would target the Barrett's stem cells for preemptive therapeutics, we performed parallel screens of small molecule libraries against Barrett's stem cells and patient-matched normal esophageal stem cells. Synthetic lethal strategies ultimately yielded drug combinations that showed low nanomolar efficacy against Barrett's stem cells that spared normal esophageal stem cells even at micromolar concentrations. The synthesis of new compositions of matter corresponding to these leads has identified powerful analogs that not only selectively eliminate stem cells of Barrett's esophagus but show similar efficacy in vitro against stem cells of LGD, HGD, and EAC. In vitro, these drug combinations show broad efficacy against Barrett's and EAC, with nanomolar elimination of 20 of 23 Barrett's cases and 6 of 7 EAC cases. In tumors derived from xenografting EAC clones, these new drug combinations show robust activity marked by tumor shrinkage and a profound loss of tumor cell clonogenicity. We foresee the potential of these synthetic lethal drug combination both as topical delivery for premetastatic lesions in the distal esophagus and perhaps as systemic applications for advanced EAC cases. Citation Format: Wa Xian, Jennifer Lin, Mona Oraei, Frank McKeon, Shan Wang, Jaffer Ajani, Christopher Crum, William Bachovchin, Melina Khorrami, Amber Su, Melika Khorrami, Shumei Song, Jeremy Siegelman, Matt Vincent, Khek Yu Ho, Yusuke Yamamoto. Drug combinations against Barrett's stem cells show efficacy across advanced lesions in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2670.
Abstract 6483: The association between food deserts, food swamps, and obesity-related cancer mortality in the United States: the new epidemic
Authors: Malcolm Bevel, Meng-Han Tsai, April Parham, Sydney Andrzejak, Samantha R. Jones, Justin X. Moore
Journal: Cancer Research (2023)

Abstract Background: Obesity-related cancers account for 40% of all cancers in the United States (U.S.). Healthy food consumption is a modifiable factor shown to reduce obesity-related cancer mortality, but residing in geographical areas with poor access to grocery stores/farmer’s markets (food deserts) or higher access to fast-food/convenience stores (food swamps) reduces healthy food access and has been severely understudied. Methods: We conducted an ecological study utilizing 2010 - 2020 data from the U.S. Department of Agriculture Food Environment Atlas and Center for Disease Control and Prevention mortality. 3,041 U.S. counties with complete information on food environment scores and obesity-related cancer mortality data were included. Food swamp score was calculated as the ratio of fast-food and convenience stores to grocery stores and farmer’s markets. Obesity-related cancer (based on the International Agency for Research on Cancer evidence between obesity and 13 types of cancer) mortality rates were categorized as high (≥71.8 per 100,000) versus low (&amp;lt;71.8 per 100,000) per county. We performed an age-adjusted multivariable polytomous logistic regression for the association between food desert scores, food swamp scores, and obesity-related cancer mortality rates. Results: Counties with high obesity-related cancer mortality rates had higher percentage of NH-black population (3.30 vs 1.80), persons older than 65 years (15.7 vs 15.4), poverty rates (19.0 vs 14.4), adult obesity rates (33.0 vs 32.1), and adult diabetes rates (12.5 vs 10.7) when compared to counties with low obesity-related cancer mortality (p-value &amp;lt; 0.0001; Table 1). We observed 77% increased odds of having high obesity-related cancer mortality rates among U.S. counties with high food swamp scores (adjusted odds ratio [AOR] = 1.77; 95% CI: 1.43 - 2.18). A positive dose-response relationship between three levels of food desert and food swamp scores and obesity-related cancer mortality was also observed (p-value &amp;lt;0.0001). Conclusions and Relevance: Policymakers, funding agencies, and community stakeholders should implement sustainable approaches at combating obesity and establishing healthier accessible food such as creating more walkable neighborhoods and community gardens. Citation Format: Malcolm Bevel, Meng-Han Tsai, April Parham, Sydney Andrzejak, Samantha R. Jones, Justin X. Moore. The association between food deserts, food swamps, and obesity-related cancer mortality in the United States: the new epidemic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6483.
Abstract 433: Mechanisms of resistance to BAY 2927088, the first reversible inhibitor targeting EGFR exon 20 insertion mutations in non-small cell lung cancer
Authors: Gizem Karsli Uzunbas, Quinn McVeigh, Akansha Gupta, Stephanie Hoyt, Andrew Cherniack, Franziska Siegel, Stephan Siegel, Matthew Meyerson, Heidi Greulich
Journal: Cancer Research (2023)

Abstract Molecular therapies targeting EGFR-mutant non-small cell lung cancer (NSCLC) have dramatically improved prognosis for patients with the classical activating mutations, L858R and exon 19 deletion. Tumors harboring EGFR exon 20 insertions do not respond to inhibitors of classical activating mutations. Agents such as amivantamab and mobocertinib have been approved for treatment of lung cancer patients with exon 20 insertions, but agents with an improved selectivity profile versus wild-type EGFR are still needed. BAY 2927088, currently in phase I clinical trials, is a novel reversible inhibitor that targets EGFR exon 20 insertion mutations with decreased activity towards wild-type EGFR. Although most patients with advanced EGFR-mutant NSCLC eventually progress due to acquired resistance to EGFR inhibitors, the mechanisms of resistance to BAY 2927088 are currently unknown. Using two different methods of in vitro resistance generation, we identified mechanisms of intrinsic and acquired resistance to BAY 2927088 and other EGFR inhibitors. With the first method, involving initial incubation with a high concentration of inhibitor, we isolated drug-tolerant persister cells that underwent a transcriptional state transition resembling EMT. With the second method, involving gradual escalation of inhibitor concentrations, we identified NRAS hotspot mutations as a mechanism of resistance to BAY 2927088 and other EGFR inhibitors. As a parallel approach, we are developing a deep-scanning mutagenesis assay of the EGFR kinase domain to identify mutations that could cause resistance. Understanding these resistance mechanisms will help to identify second-line treatments for exon 20 insertion patients who develop resistance to EGFR inhibition. Citation Format: Gizem Karsli Uzunbas, Quinn McVeigh, Akansha Gupta, Stephanie Hoyt, Andrew Cherniack, Franziska Siegel, Stephan Siegel, Matthew Meyerson, Heidi Greulich. Mechanisms of resistance to BAY 2927088, the first reversible inhibitor targeting EGFR exon 20 insertion mutations in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 433.